The ongoing burden of cardiovascular disease emphasizes the need to develop new strategies to prevent and treat atherosclerosis. Several lines of evidence indicate that a significant portion of variability in risk for atherosclerosis is heritable. However, to date family-based linkage studies and candidate gene analyses have failed to discover genetic variants that account for most of this variation. Association studies are predicted to be more efficient than linkage studies to detect genetic variants that contribute to common complex phenotypes like atherosclerosis. However, in the past, adequate genome-wide association studies have been impractical due to limitations in genotyping capacity and incomplete documentation of the common variants in the human genome. Recently, these limitations have been overcome, making it possible to design association studies with excellent power to detect common variants contributing to disease risk. These technological developments, combined with the existence of several NHLBI sponsored cohorts with detailed phenotypic data on atherosclerosis provide a highly leveraged opportunity to search for genetic variants associated with early and extensive subclinical atherosclerosis. Discovering such variants could lead to new strategies for early identification of high risk subjects when aggressive intervention would be more likely to prevent the initial development of disease. In addition, identification of variants that predispose to atherosclerosis may suggest novel pathophysiologic pathways that could be explored as potential targets for new therapeutic interventions.